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Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (p = 0.032) and advanced T stage (p = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (p = 0.0002), DFS (p < 0.0001), LRFS (p < 0.0001), and MeFS (p < 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (p = 0.015), DFS (p < 0.001), LRFS (p < 0.001), and MeFS (p < 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.
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Background
Cholangiocarcinoma (CCA) encompasses a variety of malignant tumors originating in distinct regions of the biliary tract. These tumors are classified into three categories: intrahepatic (iCCA), distal CCA (dCCA), and perihilar (pCCA), each characterized by unique causes, risk factors, molecular profiles, prognoses, and treatment approaches. CCA is considered a rare disease; its global incidence ranges from 0.3 to 6 cases per 100,000 annually, with corresponding mortality rates between 1 and 6 per 100,000 people worldwide. Notably, certain regions, such as China, South Korea, and Thailand, report higher incidence rates exceeding 6 per 100,000 [1‐3]. Over recent decades, the age-standardized incidence of iCCA has consistently risen across most regions, whereas the incidence of dCCA has declined [2]. The majority of iCCAs present as sclerosing adenocarcinomas, originating from cholangiocytes located within intralobular biliary ductules and the peribiliary glands of larger intrahepatic bile ducts [1]. Chronic conditions such as hepatitis B or C infection with associated cirrhosis [4], cholestasis, primary sclerosing cholangitis [5], and liver fluke [6] infestations are well-established risk factors for the development of cholangiocarcinoma. Additional contributors include metabolic disorders like diabetes mellitus and lifestyle or environmental influences such as alcohol consumption and smoking [7]. Recent advancements in molecular profiling have deepened our understanding of the genetic differences among CCA subtypes, uncovering distinct mutation patterns associated with specific anatomical regions [8]. Surgical resection remains the cornerstone of curative treatment for early-stage cholangiocarcinoma (CCA). However, despite advancements in understanding CCA pathogenesis, diagnostic techniques, and therapeutic strategies in recent years, patient outcomes have seen little improvement. Five-year survival rates remain low, ranging between 7 and 20%, and recurrence rates after surgical resection are significant, reaching 48 to 56% [9‐13]. Clinical factors such as tumor stage, lymph node involvement, and histological grading can help identify patients at higher risk of poor outcomes [9]. Nonetheless, the development of genomics-based prognostic biomarkers is crucial to guide postoperative treatment strategies and improve long-term prognosis.
Claudin-18.2 (CLDN18.2) is a tight junction protein primarily found in the gastric mucosa, maintaining epithelial barrier integrity. Malignant transformation disrupts cell architecture, exposing CLDN18.2 epitopes for monoclonal antibody targeting. Though normally restricted to differentiated gastric epithelial cells, CLDN18.2 is aberrantly expressed in various cancers, including those of the stomach, pancreas, esophagus, and biliary tract. Its selective overexpression in malignancies makes it a promising target for cancer therapies [14, 15]. Zolbetuximab, the first monoclonal antibody therapy targeting CLDN18.2, has demonstrated promising efficacy in clinical trials, significantly benefiting patients with CLDN18.2-positive gastric and gastroesophageal adenocarcinomas [16, 17]. These promising results underscore the potential of CLDN18.2-targeted treatments to provide improved outcomes for patients with limited therapeutic options. However, the role of CLDN18.2 in intrahepatic cholangiocarcinoma (iCCA) had not been comprehensively investigated prior to this study. Our research aims to explore the association between CLDN18.2 expression and clinical outcomes in iCCA patients following curative surgery.
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Methods
Analysis of expression profile from publicly available cholangiocarcinoma transcriptomic dataset
The cholangiocarcinoma gene expression dataset (GSE26566) comprises data from 59 non-cancerous liver samples and 104 cholangiocarcinoma tumor tissue samples, obtained from the Gene Expression Omnibus (GEO) and analyzed using the Human Genome U133 Plus 2.0 Array from Affymetrix. This dataset allows for the identification of critical genes through comparative analysis. We specifically examined gene data related to the biological process of calcium-independent cell–cell adhesion (GO:0016338). Gene expression levels were determined by combining probe data without any preselection or filtering. The genes found with significant differential expression (log2 ratio > 1, p < 0.0001) were used for identification.
Patient eligibility and enrollment
Between 1990 and 2010, a total of 182 patients with intrahepatic cholangiocarcinoma (iCCA) who underwent curative surgical resection were included in the study conducted at Chi Mei Medical Center. Patients with lymph node metastases or distant metastatic disease were excluded to ensure curative intent of the treatment. Only those with T1-3N0M0 disease were eligible for inclusion. To confirm the diagnosis and exclude other biliary system malignancies, two independent pathologists reviewed the tumor specimens. The research utilized anonymized patient samples from the biobank, with prior approval obtained from the Institutional Review Board (IRB) of Chi Mei Medical Center (approval number 09912003). All participants provided written informed consent for the collection and use of their samples, in compliance with institutional and ethical guidelines. Retrospective data, including patient demographics, clinical features, pathological details, survival outcomes, and causes of mortality, were collected for analysis. Patients with hematologic disorders, other malignancies, or incomplete clinical records were excluded from the study. Tumor staging was performed according to the eighth edition of the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) classification. The study followed the REMARK (Reporting Recommendations for Tumor Marker Prognostic Studies) guidelines for reporting prognostic tumor marker studies.
Histopathological and immunohistochemical evaluations
The T and N stages of the tumors were determined according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. The tissue specimens were processed following standardized protocols. The expression levels of CLDN18.2 were evaluated using immunohistochemistry (IHC) with an anti-CLDN18 antibody. Specifically, the investigational VENTANA CLDN18 (43-14A) RxDx IHC assay was utilized on the Ventana BenchMark Platform. To maintain objectivity, all tumor samples were reviewed by two independent pathologists blinded to the patients’ clinical details. In this study, high CLDN18.2 expression was defined as moderate-to-strong membranous staining in ≥ 75% of tumor cells, whereas low expression was defined as staining in < 75% of tumor cells (Fig. 1).
Fig. 1
The expression level of CLDN-18.2 immunohistochemical stain. High CLDN18.2 expression was defined as moderate-to-strong membranous staining in ≥ 75% of tumor cells, whereas low expression was defined as staining in < 75% of tumor cells. (scale bar = 50 μm)
The association between CLDN18.2 expression and clinicopathological parameters was assessed using the chi-square (χ2) test. Survival analysis was conducted using Kaplan–Meier survival curves, and differences in survival outcomes were assessed with the log-rank test. This analysis measured the time from surgery to either death or the last follow-up for overall survival, and to either recurrence or the last follow-up without recurrence for disease-free survival. Multivariate analysis was conducted using the Cox proportional hazards model, incorporating variables identified as clinically significant in the univariate analysis. All statistical analyses were performed using IBM SPSS Statistics software (version 22.0, Armonk, NY, USA), with a two-tailed p value of < 0.05 regarded as statistically significant.
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Results
Upregulation of CLDN18 gene links to calcium-independent cell–cell adhesion in the cholangiocarcinoma transcriptome
To facilitate data mining, we analyzed a publicly accessible cholangiocarcinoma transcriptome dataset (GSE26566), which included data from 104 patients who had undergone curative surgical resection. Our investigation identified 14 probes corresponding to ten transcripts associated with the biological process of calcium-independent cell–cell adhesion (GO:0016338) (as shown in Table 1 and Fig. 2). Among these, the CLDN18 gene (ILMN 10334) exhibited a notable increase, with a fold change of 1.5556 in log ratios (p < 0.0001) compared to adjacent liver tissues and normal intrahepatic bile ducts. Consequently, CLDN18 was selected for detailed examination in subsequent analyses.
Table 1
Summary of the alterations of gene associated with biological process calcium-independent cell–cell adhesion (GO:0016338) in cholangiocarcinoma (GSE26566)
#Comparing cholangiocarcinoma (CCA, n = 104) to surrounding liver (n = 59) and normal intrahepatic bile duct (n = 6); *statistically significant
Fig. 2
A published transcriptome dataset of intrahepatic cholangiocarcinoma (GSE26566) from GEO database showed gene expression associated with the biological process of calcium-independent cell–cell adhesion (GO:0016338). The CLDN18 is the most upregulated genes in cholangiocarcinoma compared to surrounding liver and normal biliary epithelium
CLDN18.2 is associated with poorer clinical pathological parameters of patients with intrahepatic cholangiocarcinoma
The data presented in Table 2 were obtained from a review of medical records of 182 patients diagnosed with intrahepatic cholangiocarcinoma (iCCA). Among these patients, 34 (18.7%) exhibited high CLDN18.2 expression. The majority were male (n = 108, 59%) and younger than 65 years (n = 107, 58.8%). A significant association was identified between high CLDN18.2 expression and R1 resection status (p = 0.032) and advanced T stage classification (p = 0.043). However, gender, age, hepatitis, intrahepatic lithiasis, histological variants, and histological grade showed no significant differences in the tumors of cholangiocarcinoma patients with differential CLDN18.2 expression.
Table 2
Correlations between CLDN18.2 expression and other important clinicopathological parameters in primary localized IHCC
Parameter
Category
Case no
CLDN18.2 expression
p value
Low
High
Gender
Male
108
84
24
0.139
Female
74
64
10
Age (years)
< 65
107
85
22
0.437
≥ 65
75
63
12
Hepatitis
Hepatitis B
72
60
12
0.848
Hepatitis C
29
23
6
Non-B, non-C
81
65
16
Intrahepatic lithiasis
Not identified
102
84
18
0.686
Present
80
64
16
Surgical margin
R0
163
136
27
0.032*
R1
19
12
7
Primary tumor (T)
T1
87
76
11
0.043*
T2
61
49
12
T3
34
23
11
Histological variants
Large duct type
105
83
22
0.359
Small duct type
77
65
12
Histological grade
Well differentiated
61
52
9
0.147
Moderately differentiated
66
56
10
Poorly differentiated
55
40
15
*Statistically significant
Survival analyses and clinical implications of CLDN18.2 expression
The impact of CLDN18.2 levels on tumor spread and prognosis in intrahepatic cholangiocarcinoma (iCCA) was evaluated using both univariate and multivariate analyses (Tables 3 and 4). For overall survival (OS) and disease-specific survival (DFS) (Table 3), male patients showed a higher number of events than females, but this was not significant in the multivariate analysis. R1 resection, higher tumor stage, and high CLDN18.2 expression were significantly associated with poor survival. For local recurrence-free survival (LRFS) and metastasis-free survival (MFS) (Table 4), R1 resection, advanced tumor stage, histological variants, differentiation, and CLDN18.2 were significantly linked to a higher recurrence risk. Among them, histological variants and differentiation was significantly associated with local recurrence-free survival in univariate analyses but not in multivariate analyses. These findings suggest that CLDN18.2 overexpression is a key independent predictor of poor prognosis, increasing risks of recurrence, metastasis, and reduced survival, further supporting its potential as a therapeutic target in iCCA.
Table 3
Univariate log-rank and multivariate analyses for overall and disease-specific survivals in primary localized IHCC
Parameter
Category
Case no
Overall survival
Disease-specific survival
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
No. of event
p value
R.R
95% C.I
p value
No. of event
p value
R.R
95% C.I
p value
Gender
Male
108
50
0.0254*
1
-
0.119
9
0.0072*
1
-
0.114
Female
74
21
1.511
0.900–2.539
-
32
1.160
0.865–3.889
-
Age (years)
< 65
107
37
0.2626
-
-
-
28
0.2125
-
-
-
≥ 65
75
34
-
-
-
13
-
-
-
Hepatitis
Hepatitis B
72
32
0.2379
-
-
-
16
0.4561
-
-
-
Hepatitis C
29
8
-
-
-
19
-
-
-
Non-B, non-C
81
31
-
-
-
6
-
-
-
Intrahepatic lithiasis
Not identified
102
36
0.2831
-
-
-
19
0.1613
-
-
-
Present
80
35
-
-
-
22
-
-
-
Surgical margin
R0
163
59
< 0.0001*
1
-
0.004*
31
< 0.0001*
1
-
< 0.001*
R1
19
12
2.751
1.393–5.432
10
2.120
2.215–11.029
Primary tumor (T)
T1
87
25
0.0001*
1
-
0.004*
9
< 0.0001*
1
-
0.004*
T2
61
27
1.768
1.020–3.065
-
19
3.555
1.595–7.920
-
T3
34
19
2.468
1.305–4.667
-
13
3.699
1.535–8.914
-
Histological variants
Large duct type
105
43
0.4281
-
-
-
27
0.1984
-
-
-
Small duct type
77
28
-
-
-
14
-
-
-
Histological grade (differentiation)
Well
61
20
0.1663
-
-
-
12
0.3881
-
-
-
Moderately
66
28
-
-
-
16
-
-
-
Poorly
55
23
-
-
-
13
-
-
-
CLDN18.2 Exp
Low expression
91
25
0.0002*
1
-
0.015*
10
< 0.0001*
1
-
< 0.001*
High expression
91
46
2.002
1.146–3.498
-
31
4.524
2.324–8
-
*Statistically significant
Table 4
Univariate log-rank and multivariate analyses for local recurrence-free and metastasis-free survivals in primary localized IHCC
Parameter
Category
Case no
Local recurrence-free survival
Metastasis-free survival
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
No. of event
p value
R.R
95% C.I
p value
No. of event
p value
R.R
95% C.I
p value
Gender
Male
108
54
0.2170
-
-
-
21
0.1008
-
-
-
Female
74
31
-
-
-
44
-
-
-
Age (years)
< 65
107
55
0.2993
-
-
-
42
0.2936
-
-
-
≥ 65
75
30
-
-
-
23
-
-
-
Hepatitis
Hepatitis B
72
33
0.7333
-
-
-
26
0.8762
-
-
-
Hepatitis C
29
13
-
-
-
11
-
-
-
Non-B, non-C
81
39
-
-
-
28
-
-
-
Intrahepatic lithiasis
Not identified
102
41
0.0551
-
-
-
31
0.1000
-
-
-
Present
80
44
-
-
-
34
-
-
-
Surgical margin
R0
163
71
< 0.0001*
1
-
0.011*
54
< 0.0001*
1
0.017*
R1
19
14
3.233
1.657–6.306
11
2.389
1.171–4.870
Primary tumor (T)
T1
87
28
< 0.0001*
1
-
0.012*
21
< 0.0001*
1
-
0.007*
T2
61
32
1.652
0.957–2.853
26
2.074
1.061–4.053
T3
34
25
2.449
1.352–4.438
18
2.490
1.390–4.460
Histological variants
Large duct type
105
58
0.0085*
1
-
0.320
43
0.0759
-
-
-
Small duct type
77
27
0.781
0.479–1.272
22
-
-
-
Histological grade (differentiation)
Well
61
28
0.0299*
1
-
0.275
22
0.1794
-
-
-
Moderately
66
27
0.872
0.504–1.508
22
-
-
-
Poorly
55
30
1.363
0.792–2.346
21
-
-
-
CLDN18.2 exp
Low expression
91
22
< 0.0001*
1
-
< 0.001
13
< 0.0001*
1
-
< 0.001*
High expression
91
63
3.559
2.180–5.810
52
7.813
4.464–13.677
*Statistically significant
Survival analysis in intrahepatic cholangiocarcinoma
Kaplan–Meier survival analysis demonstrated that elevated CLDN18.2 expression was significantly associated with poorer outcomes in patients with intrahepatic cholangiocarcinoma (iCCA). High CLDN18.2 expression was associated with decreased overall survival (OS) (Fig. 3A; p = 0.0002), disease-specific survival (DSS) (Fig. 3B; p < 0.0001), local recurrence-free survival (LRFS) (Fig. 3C; p < 0.0001), and metastasis-free survival (MFS) (Fig. 3D; p < 0.0001).
Fig. 3
Kaplan–Meier analysis showed CLDN18.2 overexpression associated with A worse overall survival, B worse disease-specific survival, C worse local recurrence-free survival, and D worse metastasis-free survival in iCCA patients
Claudin-18.2 (CLDN18.2), a tight junction protein primarily expressed in nonmalignant gastric epithelium, becomes exposed on the surface of tumor cells during malignant transformation, making it an attractive target for cancer therapies. Tight junction proteins, such as claudins, are essential for maintaining cell-to-cell adhesion, regulating the movement of molecules across cells, and preserving cellular polarity [18]. Disruptions in claudin expression can impair tight junction function, interfere with cellular signaling pathways, and potentially drive tumorigenesis in epithelial cancers [14, 19‐21]. Aberrant regulation of claudins has been observed in various malignancies, including gastric [22‐24], hepatocellular, biliary tract, breast, renal, pancreatic, non-small cell lung cancers, and mesothelioma [25‐29].
Previous studies have explored the prognostic significance of CLDN18.2 in various malignancies. In gastric cancer, loss of CLDN18.2 has been associated with poorer survival [30, 31], whereas in pancreatic cancer, its expression correlates with lymph node metastasis and tumor grade but not overall survival [32‐34]. Additionally, in endocervical adenocarcinoma, CLDN18.2 expression has been linked to worse progression-free survival [35]. Our study extends these findings to intrahepatic cholangiocarcinoma (iCCA), demonstrating that high CLDN18.2 expression is associated with poorer disease-free and metastasis-free survival. These results suggest that the impact of CLDN18.2 varies by cancer type, possibly due to its dual role as either a tumor suppressor or promoter depending on the tumor types [33, 36‐43].
Recent studies have shown that claudin-18 is expressed in a significant proportion of cholangiocarcinomas. In primary tumors, approximately half were found to be positive for claudin-18, while 57% of cases in the metastatic cohort exhibited positivity [44]. Another study reported that only 6.3% of biliary tract cancer patients tested positive for CLDN18.2 [45]. Shinozaki et al. reported that the CLDN18.2 positivity rate was higher in extrahepatic cholangiocarcinoma compared to intrahepatic cholangiocarcinoma (90% vs. 43%). Additionally, their findings indicated that CLDN18.2-positive iCCA cases were associated with more aggressive tumor characteristics, including periductal infiltrative growth, perineural invasion, and lymph node metastasis. They concluded that CLDN18.2 expression in iCCA correlates with poor prognosis and aggressive behavior, which aligns with our findings [46]. In our study, 18.7% of patients demonstrated high CLDN18.2 expression. However, our cohort exclusively included non-metastatic iCCA patients, with specimens derived solely from primary tumors. It is important to note that the cutoff thresholds for CLDN18.2 expression and the antibodies used to detect it varied across these studies. In our research, we adopted the criteria used in the ILUSTRO, SPOTLIGHT, and GLOW clinical trial [16, 17, 47], defining high expression as membrane staining in more than 75% of cells and employing the same CLDN18.2 immunohistochemistry assay as the clinical trial to facilitate future clinical applications.
Zolbetuximab, a chimeric IgG1 monoclonal antibody, targets CLDN18.2 on cancer cells, inducing cell death via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). It has shown efficacy in phase II trials [16, 24, 48] and significantly improved survival in the phase III SPOTLIGHT and GLOW study for metastatic gastric cancer [17, 47]. Other CLDN18.2-targeted therapies, including chimeric antigen receptor (CAR)-T cells [49, 50], bifunctional antibodies, and antibody–drug conjugates (ADCs), are rapidly advancing in clinical trials [51, 52]. As ADCs may be effective in tumors with low CLDN18.2 expression, while monoclonal antibodies work best in high-expression cases [53], determining CLDN18.2 levels across cancers is essential for optimizing treatment strategies.
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Our study has several limitations. First, it is a single-center retrospective analysis without experimental validation. Second, we conducted data mining using the transcriptome dataset GSE26566 from the Gene Expression Omnibus (GEO). While GSE26566 is a transcriptome dataset for cholangiocarcinoma rather than exclusively intrahepatic cholangiocarcinoma (iCCA), we selected it over the alternative iCCA dataset, GSE32225, for the following reasons: (1) GSE32225 lacks normal tissue for comparison, which is essential for our research focus and (2) GSE32225 is based on formalin-fixed ICC samples, which are less reliable than the snap-frozen tissues used in GSE26566. However, this choice may introduce certain limitations to our study. Additionally, the study exclusively analyzed primary tumor tissues from non-metastatic intrahepatic cholangiocarcinoma (iCCA) patients, limiting the generalizability of our findings on CLDN18.2 expression to metastatic scenarios. Furthermore, the absence of a standardized method for the immunohistochemical assessment and quantification of CLDN18.2 poses challenges in establishing consensus within the field. Lastly, while our study identifies CLDN18.2 as a prognostic factor, its precise role in cancer treatment remains uncertain. With the ongoing development of CLDN18.2-targeted therapies and immunotherapy agents, as well as active clinical trials, we anticipate that future trial results will provide greater clarity on its therapeutic potential.
Conclusion
In conclusion, the evidence presented in our investigation reveals a significant correlation between upregulated expression of CLDN18.2 and the presence of advanced clinical-pathological features in intrahepatic cholangiocarcinoma. Furthermore, high CLDN18.2 expression has emerged as a prognostic biomarker, indicating adverse outcomes in intrahepatic cholangiocarcinoma patients.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Chi-Mei Medical Center with approval number 09912003.
Consent for publication
Informed consent was obtained from all subjects involved in the study.
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Competing interests
The author declares no competing interests.
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